Effects of mycophenolate mofetil on chronic allograft nephropathy by affecting RHO/ROCK signal pathways.
OBJECTIVE
We sought to investigate the effects of mycophenolate mofetil (MMF) on chronic allograft nephropathy (CAN) by affecting Rho and ROCK signal pathways.


METHODS
Male inbred F344 rat renal grafts orthotopically transplanted into Lewis rats were first treated with CsA (10 mg/kg(-1).d(-1) x 10 d) and then divided into 3 groups (each n = 9): (1) orally vehicle, (2) cyclosporine (CsA, 6 mg/kg(-1).d(-1)) and (3) MMF (20 mg/kg(-1).d(-1)). In addition we performed autografts of F344 (n = 10) at 4, 8, and 12 weeks, serum creatinine (SCr) was measured and pathologic changes assessed. Expression of RhoA and ROCK-1 was determined by real-time reverse transcriptase polymerase chain reaction. Expressions of alpha-smooth muscle actin (alpha-SMA) and connective tissue growth factor (CTGF) were observed by immunohistochemistry.


RESULTS
SCr and Banff score began to increase at 4 weeks in all 3 allografted groups with obvious deterioration in both the vehicle and CsA groups at 8 and 12 weeks. The differences between vehicle/CsA and autografts were significant (P = .000). SCr and Banff score among the MMF group increased mildly and moderately at 8 and 12 weeks, respectively, but were significantly lower than those in the vehicle/CsA cohort (P < .05). Expressions of RhoA and ROCK-1 mRNAs and proteins were observed in mesangial and tubular cells, increasing gradually along with the progression of chronic allograft nephropathy (CAN). There was a negative correlation between RhoA/ROCK-1 mRNA and Banff score (r = -.637, p = .000; r = -.676, P = .000) or SCr (r = -.705, P = .000; r = -.756, P = .000). MMF downregulated gene and protein expressions of RhoA and ROCK-1. CsA had little effect on these expressions. Expressions of alpha-SMA and CTGF were observed in renal epithelial and tubular cells.


CONCLUSIONS
Herein we have demonstrated abnormal expression of RhoA and ROCK-1 signal pathways, which may play roles in CAN. MMF may attenuate CAN by downregulating the expression of RhoA/ROCK-1, alpha-SMA, and CTGF.
Song
J
J
Transplantation Institute, West China Hospital, Sichuan University, China.
Lu
Y P
YP
Luo
G H
GH
Yang
L
L
Ma
X
X
Xia
Q J
QJ
Shi
Y J
YJ
Li
Y P
YP
D000818:Animals; D003404:Creatinine / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D007700:Kinetics; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014184:Transplantation, Homologous; D054460:rho-Associated Kinases / Q000235:genetics* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D003404:Creatinine; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D009173:Mycophenolic Acid